Epilepsy is among the most common serious neurological disorders. Our current research has focused on mechanisms of seizure generation using a unique parallel reiterative animal/human research paradigm in an effort to identify targets for novel antiseizure therapies to treat these pharmacoresistant patients. We have succeeded in defining electrophysiological disturbances in patients with mesial temporal lobe epilepsy (MTLE), and rat models of this disorder, at the local field potential (LFP) and unit levels, and identified pathological high- frequency oscillations (pHFOs) as biomarkers of epileptic brain tissue. Evidence that pHFOs reflect summated action potentials of small clusters of pathologically interconnected synchronously bursting neurons (PIN clusters) that are spatially stable over time, but expand with changes in the local microenvironment, has led to the hypothesis that spontaneous seizures result from coalescence and synchronization of PIN clusters. We are now also identifying similar pathological changes in perilesional neocortex in rats with posttraumatic epilepsy (PTE), following fluid percussion injury (FPI), in order to study mechanisms of epileptogenesis that might suggest preventive, and disease-modifying, interventions for patients with traumatic brain injury (TBI). A major innovation of the animal work proposed here is the fabrication of MRI-compatible carbon fiber microelectrodes capable of recording pHFOs and multiunit activity, permitting simultaneous continuous electrophysiological monitoring and repeated diffusion tensor imaging (DTI) and functional MRI (fMRI) investigations over many months to identify and localize structural and functional disturbances that distinguish rats that later develop PTE from those that do not. We also will be using these microelectrode and neuroimaging data in an effort to identify pathological features of surface EEG that could be used as noninvasive biomarkers of epileptogenesis clinically, as patients with TBI, unlike those with MTLE, are not usually subjected to invasive EEG evaluations. Our overarching hypothesis is that specific neuronal populations are responsible for epileptogenesis and ictogenesis, and that their characterization and localization will lead to clinically useful biomarkers and novel targets for intervention. Aim 1 is a new research direction: to monitor EEG, HFOs, multiunit activity, DTI, and fMRI after injury in the rat to identify and localize changes that predict the development of spontaneous epileptic seizures. Aims 2 and 3 are continuations of current research: to monitor EEG, LFPs, and multiunit activity in the PTE rat to identify and localize functional changes that occur at onset of seizures for comparison with data obtained from MTLE rat models; and to monitor EEG, LFPs, and multiunit activity in patients with MTLE to identify and localize functional changes in neuronal elements that occur at the onset of seizures for comparison with data obtained from rats. Long-term objectives will include utilization of these results to establish biomarkers of epileptogenesis and predictors of ictogenesis, and to identify targets for novel interventions to treat, prevent, and cure epilepsy.